Seropositivity for celiac disease in children and adolescents
with short stature
Soropositividade para doença celíaca em crianças e adolescentes com baixa estatura
Ana Carla L. N. Gueiros1, Giselia Alves P. Silva2
Objective: To assess the frequency of positive serological Objetivo: Avaliar a frequência da positividade do marca-
marker for celiac disease in children and adolescents with dor sorológico para doença celíaca em crianças e adolescentes
short stature using the human antibody anti-transglutami- com baixa estatura, utilizando-se o anticorpo anti-transglu-
nase as a screening test. taminase humana como teste de triagem.
Methods: This cross-sectional study was conducted from Métodos: Estudo descritivo com amostra obtida por
April to September/2004 with 78 children and adolescents conveniência. Foi realizado no período de abril a setembro
selected by convenience when attending the outpatient de 2004 no Ambulatório Geral de Pediatria do Instituto Ma-
clinic of two university hospitals of Recife, Northeast Bra- terno Infantil Professor Fernando Figueira e no Ambulatório
zil. Cases were children and adolescents with short stature, de Crescimento e Desenvolvimento do Hospital das Clínicas.
defined as height-for-age and sex below the 3rd percentile Foram considerados casos as crianças e os adolescentes por-
of the National Center for Health Statistics (NCHS, 2000) tadores de baixa estatura, definida como aquela abaixo do
growth curve. The human antibody anti-transglutaminase percentil 3 para idade e sexo, utilizando como referência o
(AATGh) was defined as positive when >20U/mL. For gráfico de altura/idade do National Center for Health Statistics,
those with a positive result, IgA anti-endomysial antibody 2000. Foi pesquisado o anticorpo anti-transglutaminase hu-
was assessed. Results: Out of the 78 patients evaluated, mana (AATGh), considerado positivo se concentração >20U/
41 (53%) were females. The AATGh was positive in 3/78 mL e, nos positivos, o anticorpo antiendomísio (AAE).
(3.8%) patients. The IgA anti-endomysial antibody was Resultados: Foram avaliados 78 pacientes, sendo 41
positive in one patient, who had the highest AATGh con- (53%) do sexo feminino. O AATGh foi positivo em 3/78
centration. Taking those with positivity for both tests, the (3,8%) dos pacientes. O AAE foi positivo em um pacien-
seropositivity was 1.3%. te, naquele com concentração mais elevada do AATGh.
Conclusions: The presence of serological marker of Considerando-se a positividade para os dois testes, a soro-
celiac disease in children and adolescents with low stature positividade foi de 1,3%.
of low-income families highlights the need for systematic Conclusões: A presença de marcador sorológico para
investigation of celiac disease in these patients. doença celíaca em crianças e adolescentes portadoras de baixa-
estatura e pertencentes a famílias de baixa-renda aponta para
Key-words: failure to thrive; celiac disease; child; a necessidade de investigação sistemática da doença celíaca
adolescent. nesses pacientes.
Institution: Universidade Federal de Pernambuco (UFPE) e Instituto Materno Corresponding author:
Infantil Professor Fernando Figueira (IMIP), Recife, PE, Brasil Giselia Alves P. Silva
Mestre em Saúde da Criança e do Adolescente pela UFPE, IMIP, Recife, Rua Simão Mendes, 195/202 – Jaqueira
PE, Brasil CEP 52050-110 – Recife/PE
Doutora em Pediatria pela Escola Paulista de Medicina da Universidade E-mail: firstname.lastname@example.org
Federal de São Paulo (Unifesp-EPM), professora-associada de Pediatria
da UFPE, Recife, PE, Brasil Financial Support: ACG foi bolsista da Coordenação de Aperfeiçoamento
de Pessoal de Nível Superior (Capes)
Submission: Jul 29, 2008
Approval: Oct 25, 2008
Rev Paul Pediatr 2009;27(1):28-32.
Ana Carla L. N. Gueiros et al
Palavras-chave: insuficiência de crescimento; doença anti-tissue transglutaminase (anti-tTG) as a screening test
celíaca; criança; adolescente. for celiac disease.
Short stature has a variety of different causes and its emer- This was a cross-sectional, descriptive study carried out
gence is dependent on multiple factors: genetic programming, between April and September 2004 at the General Pediat-
endocrine factors and environmental influences. Environment, rics Clinic at Instituto Materno-Infantil Professor Fernando
in this context, encompasses not only the physical, but also Figueira (IMIP) and at the Growth and Development Clinic
the psychosocial, economic and nutritional environment(1,2). at Hospital das Clínicas, Universidade Federal de Pernam-
This is a complex phenomenon which, in the majority of cases, buco, Recife, northeast of Brazil.
is the result of multiple causative mechanisms. Children and adolescents aged 2 to 20 years were defined
The causes of short stature are described as primary when as short stature cases if their heights were below the third
there is an abnormality in the potential for bone growth, as percentile for their age and sex according to the height/age
in bone diseases(2). In the presence of secondary causes, the curves published by the National Center for Health Statistics
potential for bone growth is unaltered, but there are factors (NCHS), 2000(15). Patients were excluded if they were less
that prevent this potential from being expressed, including than two years old, had been diagnosed with bone metabolism
malnutrition and systemic diseases(2). diseases, bone dysplasia, intrauterine growth restriction, dys-
Celiac disease is characterized by permanent gluten in- morphic syndromes, chromosome diseases, metabolite storage
tolerance in people who are genetically susceptible. Gluten diseases, endocrine disorders (hypopituitarism, hypothyroid-
provokes an inflammatory reaction that damages the villi ism, diabetes mellitus, Cushing’s disease, hypogonadism), or
in the small intestine, causing an inadequate absorption of chronic renal failure, or if they had been using oral, intra-
nutrients. The disease has a varied spectrum of presentations, venous or intramuscular glucocorticoids for a period greater
ranging from the classic form (chronic diarrhea, abdominal than eight days, amphetamines or methylphenidate.
pain and distension, weight loss, failure to thrive and signs All guardians were informed and agreed to participate
of malnutrition) to atypical and silent forms with no gas- in the study, and signed a free and informed consent form.
trointestinal symptoms(3,4). There was only one refusal, because the child would not
A great deal of research has been carried out into short accept blood being taken. The study was approved by the
stature in isolation as an atypical form of presentation of celiac Human Research Ethics Committee at IMIP.
disease. Studies have reported varying frequencies (from 1.7 Anthropometric data, weight and height, were measured
to 59.1%), depending on the selection criteria adopted, the with children unclothed, with no shoes or socks, using a digital
study location and the diagnostic approach employed(5-13). balance accurate to 0.1kg and a wall-mounted stadiometer ac-
Screening patients with short stature for celiac disease is not curate to 0.1cm. After measurement, a structured questionnaire
part of the medical routine in our country, since these tests are was administered covering socioeconomic and demographic
expensive and not always available on the Brazilian National aspects as well as complaints related to celiac disease (abnormal
Health System (SUS, Sistema Único de Saúde). Notwithstand- intestinal rhythm, abdominal pains, flatulence, recurrent aph-
ing, there is already consensus that children and adolescents thous ulcers, difficulty gaining weight and height, irritability,
with short stature should be serologically screened for celiac history of anemia, other cases of celiac disease in the family).
disease. This recommendation is included in guidelines pub- Blood for serology was collected by venous puncture into
lished by the Pediatric Gastroenterology Department of the tubes with no anticoagulant, which were then centrifuged to
Brazilian Society of Pediatrics (SBP - Sociedade Brasileira de separate serum. Samples were subdivided and frozen at -20º
Pediatria) and by the North American Society for Pediatric C, until laboratory tests were carried out. Initial screening
Gastroenterology, Hepatology and Nutrition(14). was carried out using anti-tTG assays; where these were posi-
The objective of this study was to determine the fre- tive, anti-endomysial antibody (AEA) was assayed as well.
quency of positive serological assay results in children and Enzyme immunoassay (Biosystems, Spain) was used to
adolescents with short stature, selected at outpatients clin- determine IgA tTG using microplate tests. Samples with
ics affiliated with SUS in the city of Recife, using human concentrations >20U/mL were defined as positive(16). Indirect
Rev Paul Pediatr 2009;27(1):28-32. 29
Seropositivity for celiac disease in children and adolescents with short stature
immunofluorescence was used to determine AEA, using histo- Based on both anti-tTG and AEA being positive, the rate
logical sections of distal monkey esophagus fixed on microscope of seropositivity was 1.3%.
slides as substrate (Biosystems, Spain). Uniform fluorescence Clinical and laboratorial characteristics of the anti-tTG-
in 1/5 saline solution dilution was defined as positive. Patients positive patients are given in Chart 1.
with positive anti-tTG serology were referred to the gastroen-
terology clinic to continue investigation of celiac disease. Discussion
Data were stored in Epi-Info version 6.0. Seropositivity
was calculated as the proportion of individuals in the sample This study was carried out at teaching hospitals affiliated
with positive serology. with SUS. IMIP is a philanthropic hospital, and Hospital das
Clínicas belongs to Universidade Federal de Pernambuco.
Results The great majority of people treated at both hospitals come
from deprived populations.
A total of 78 patients were evaluated between April and The rate of seropositivity for anti-tTG was 3.8%, while
September of 2004; 41 (53%) were female and 37 (47%) AEA was only positive in the patient who showed the highest
were male. Median age was 9 years (P25=5 years, P75=12 anti-tTG concentration. The administration of two serologi-
years). Forty-five (58%) of the 78 study participants came cal tests in series contributed to refining diagnostic prob-
from Recife and the metropolitan area, while 33/78 (42%) ability. It is important to point out that, to date, diagnosis
lived in provincial parts of the state of Pernambuco. Among of celiac disease is still based on observation of histological
the patients included, 72% came from families with a abnormalities; biopsy is an invasive and expensive method
monthly income of two times the minimum monthly wage which is not appropriate for initial investigation(14). Fur-
or less, and approximately 63% of the guardians had not thermore, the wide spectrum of celiac disease and its non-
completed primary education. specific clinical manifestations make it difficult to identify
Seventeen (22%) of these children were classed as under- patients who require biopsy(14). Over recent years, attempts
weight on the basis of the relationship between body mass have been made to find other diagnostic methods with good
index (BMI) and age, i.e., they were below the 5th percentile sensitivity and specificity for the screening and diagnosis
of the reference standard. With relation to complaints, 58/78 of celiac patients.
(74%) of the mothers said their children had difficulty gain- The anti-tTG assay emerged as a great hope for celiac
ing weight, 67/78 (86%) reported failure to thrive and 47/78 disease screening, since it is an easily-executed test with
(60%) of the children had a history of anemia. a relatively low cost and can be used in screening stud-
The anti-tTG assays were positive in 3.8% of cases ies, with similar results to those obtained using AEA,
(3/78). These patients had AEA assayed as well, and one which is considered the best serological test for this
of them resulted positive. The patient who was positive disease(14,16-18). The AEA takes longer, costs more and is
for AEA had also had the highest anti-tTG concentration. operator-dependent, which can lead to errors(14,17,19,20).
Chart 1 – Physical and laboratorial characteristics and signs and symptoms of anti-tTG-positive patients with short stature
Sex Age Height BMI Anti-tTG AEA Signs and symptoms
Fem 7 years, 112.7cm Between 44.167 Negative Occasional abdominal pain,
9 months P10-P25 difficulty gaining weight
and height. Prior history of
Fem 12 years, 139.5cm <P5 55.065 Negative Difficulty gaining weight
10 months and height. Prior history of
Fem 11 years, 129.0cm Between 152.007 Positive Frequent abdominal pain,
8 months P10-P25 difficulty gaining weight
and height. Prior history of
BMI: body mass índex; AEA: anti-endomysial antibody.
30 Rev Paul Pediatr 2009;27(1):28-32.
Ana Carla L. N. Gueiros et al
Based on the available evidence and on practical consid- is an important suggestion, particularly for locations where
erations, anti-tTG is the primary test recommended for resources are scarce, the study requires further investigation
screening(14,19). The North American Society for Pediatric and its reproducibility must be confirmed.
Gastroenterology, Hepatology and Nutrition(14) recom- Celiac disease used to be considered rare in Brazil, and
mends the anti-tTG as the initial screening test for groups there was a scarcity of studies into its prevalence. It is only
at risk of celiac disease, followed by intestinal biopsy. If in recent years that short stature has come to be investigated
histological findings are not consistent with celiac disease, as a clinical presentation of the disease(6,28-30). Queiroz et al(6)
it is recommended that the biopsy be re-evaluated by an found a celiac disease prevalence of 4.7% among patients
experienced pathologist and that consideration be given to with short stature who had already undergone in-depth
testing AEA, asssaying human leukocyte antigen (HLA) investigation at a specialized center.
or repeating the biopsy. Among low-income populations, short stature is very of-
Several different studies have compared AEA with ten attributed to living conditions and chronic malnutrition.
anti-tTG in terms of sensitivity and specificity and have The effect of environment on growth is well established(31-34).
concluded that they are similar(21). In patients with little It is known that unhealthy living conditions and chronic
or no symptomology, both tests offer a positive predictive malnutrition are negative stimuli and that the malnutrition
value (PPV) of 75-80%, approaching 100% in symptomatic caused by poverty is most obviously manifest in failure to
patients(14,21,22). thrive(32,33). Celiac disease also affects these patients and
Several different studies(14,20,21,23-25) have shown that the may aggravate malnutrition. In a study carried out at IMIP,
accuracy of serological tests may not be as good in clinical seroprevalence of celiac disease was 1.9%, based on positive
practice as research suggests. Some authors have related AEA anti-tTG and AEA antibodies(35). The fact that that study
positivity with the degree of villous atrophy rather than with was carried out at a pediatric hospital which is a center of
clinical symptomology, which may reduce the number of excellence in the state of Pernambuco may have introduced
cases positive for celiac disease, particularly where villous a prevalence bias, since at these services there is a greater
atrophy is less severe(14,25,26). Seronegative cases of celiac probability of undiagnosed patients under investigation for
disease do occur; these patients have a clinical presentation clinical conditions compatible with celiac disease (anemia,
with symptoms and response to gluten-free diets similar to short stature, and abdominal pains)(35).
those observed in seropositive patients(25). Celiac disease is a cause of short stature that should not
Some authors(20,22) recommend the performance of serial be forgotten, particularly in deprived populations, and
serological tests before indicating biopsy: first, anti-tTG; must be borne in mind during diagnostic investigations.
when positive, confirmation using AEA. In a recent article, It is important to point out that serological tests are not
Barker et al(27) suggested using anti-tTG as a screening test. performed as part of the SUS service in Pernambuco, which
These authors indicate the performance of biopsies in chil- impacts negatively on diagnosis. Considering that anti-tTG
dren with levels >20U/mL and <100U/mL, since diagnostic assays identify IgA antibodies, it is important to confirm
precision is limited within this range. Values >100U/mL serum IgA levels in patients with clinical signs compatible
were associated with histological abnormalities caused by with celiac disease and negative serology. A small intestine
celiac disease, and the authors do not believe that these biopsy is an indispensable part of the sequence of diagnostic
patients require biopsy, thus reducing costs(27). While this investigation of seropositive patients(36).
1. Marcondes E, Setian N, Carraza FR. Desenvolvimento físico (crescimento) e Adolesc Health Care 2007;37:86-105.
funcional da criança. In: Marcondes E, Vaz FC, Ramos JA, Okay Y, editores. 4. Murray JA. The widening spectrum of celiac disease. Am J Clin Nutr
Pediatria básica. 9ª ed. São Paulo: Servier; 2002. p. 23-35. 1999;69:354-65.
2. Longui CA. Crescimento. In: Monte O, Lonqui CA, Calliari SE. Endocrinologia 5. Rossi TM, Albini CH, Kumar V. Incidence of celiac disease identified by the
para o pediatra. 2ª ed. São Paulo: Atheneu; 1998. p. 3-10. presence of serum endomysial antibodies in children with chronic diarrhea, short
3. Mearin ML. Celiac disease among children and adolescents. Curr Probl Pediatr stature, or insulin-dependent diabetes mellitus. J Pediatr 1993;123:262-4.
Rev Paul Pediatr 2009;27(1):28-32. 31
Seropositivity for celiac disease in children and adolescents with short stature
6. Queiroz MS, Nery M, Cançado EL, Gianella-Neto D, Liberman B. Prevalence 21. Hill ID. What are the sensitivity and specificity of serologic tests for celiac
of celiac disease in Brazilian children of short stature. Braz J Med Biol Res disease? Do sensitivity and specificity vary in different populations?
2004;37:55-60. Gastroenterology 2005;128:S25-32.
7. Stenhammar L, Fällström SP, Jansson G, Jansson U, Lindberg T. Coeliac 22. Hoffenberg EJ. Should all children be screened for celiac disease?
disease in children of short stature without gastrointestinal symptoms. Eur J Gastroenterology 2005;128(4 Suppl 1):S98-103.
Pediatr 1986;145:185-6. 23. Murray JA, Herlein J, Mitros F, Goeken JA. Serologic testing for celiac disease
8. Cacciari E, Salardi S, Lazzari R, Cicognani A, Collina A, Pirazzoli P et al. Short in the United States: results of a multilaboratory comparison study. Clin Diagn
stature and celiac disease: a relationship to consider even in patients with no Lab Immunol 2000;7:584-7.
gastrointestinal tract symptoms. J Pediatr 1983;103:708-11. 24. Kwiecien J, Karczewska K, Lukasik M, Kasner J, Dyduch A, Zabka A et al.
9. Tümer L, Hasanoglu A, Aybay C. Endomysium antibodies in the diagnosis Negative results of antiendomysial antibodies: long term follow up. Arch Dis
of celiac disease in short-stature children with no gastrointestinal symptoms. Child 2005;90:41-2.
Pediatr Int 2001;43:71-3. 25. Abrams JA, Diamond B, Rotterdam H, Green PH. Seronegative celiac disease:
10. Groll A, Candy DC, Preece MA, Tanner JM, Harries JT. Short stature as the increased prevalence with lesser degrees of villous atrophy. Dig Dis Sci
primary manifestation of coeliac disease. Lancet 1980;2:1097-9. 2004;49:546-50.
11. Rosenbach Y, Dinari G, Zahavi I, Nitzan M. Short stature as the major 26. Ozgenc F, Aksu G, Aydogdu S, Akman S, Genel F, Kutukculer N et al.
manifestation of celiac disease in older children. Clin Pediatr (Phila) Association between anti-endomysial antibody and total intestinal villous
1986;25:13-6. atrophy in children with celiac disease. J Postgrad Med 2003;49:21-4.
12. Bonamico M, Sciré G, Mariani P, Pasquino AM, Triglione P, Scaccia S et al. 27. Barker CC, Mitton C, Jevon G, Mock T. Can tissue transglutaminase antibody
Short stature as the primary manifestation of monosymptomatic celiac disease. titers replace small-bowel biopsy to diagnose celiac disease in select pediatric
J Pediatr Gastroenterol Nutr 1992;14:12-6. populations? Pediatrics 2005;115:1341-6.
13. Giovenale D, Meazza C, Cardinale GM, Sposito M, Mastrangelo C, Messini 28. Oliveira MC, Reis FJ, Chagas AJ, Brasileiro Filho G, Bahia M, Silva LD et al.
B et al. The prevalence of growth hormone deficiency and celiac disease in Estudo de doenças de má absorção intestinal como causa de baixa estatura
short children. Clin Med Res 2006;4:180-3. monossintomática. J Pediatr (Rio J) 1998;74:213-6.
14. Hill ID, Dirks MH, Liptak GS, Colletti RB, Fasano A, Guandalini S et al. Guideline 29. Guandalini S. Celiac disease in the new world. J Pediatr Gastroenterol Nutr
for the diagnosis and treatment of celiac disease in children: recommendations 2000;31:381-6.
of the North American Society for Pediatric Gastroenterology, Hepatology and 30. Mandal A, Mayberry J. How Common Is Celiac Disease in South America?
Nutrition. J Pediatr Gastroenterol Nutr 2005;40:1-19. AM J Gastroenterol 2000;95:579-80.
15. Centers for Disease Control and Prevention [homepage on the Internet]. CDC 31. Zeferino AM, Barros Filho AA, Bettiol H, Barbieri MA. Monitoring growth. J
growth charts: United States [cited 2003 May 10]. Available from: http://www. Pediatr (Rio J) 2003;79(Suppl 1):S23-32.
cdc.gov/growthcharts 32. Aerts D, Drachler ML, Giugliani ER. Determinants of growth retardation in
16. Wong RC, Wilson RJ, Steele RH, Radford-Smith G, Adelstein S. A comparison Southern Brazil. Cad Saude Publica 2004;20:1182-90.
of 13 guinea pig and human anti-tissue transglutaminase antibody ELISA kits. 33. Benigna MJ, Dricot J, D’Ans CD. Crescimento e estado nutricional de crianças
J Clin Pathol 2002;55:488-94. de 0-11 anos, Estado da Paraíba (Nordeste Brasileiro). Rev Saude Publica
17. Baudon JJ, Johanet C, Absalon BY, Morgant G, Cabrol S, Mougenot JF. 1987;21:480-9.
Diagnosing celiac disease. Arch Pediatr Adolesc Med 2004;158:584-8. 34. Vieira MF, Solymos GM, Souza MH, Ferrari AA, Unegbu H, Sawaya AL.
18. Carroccio A, Vitale G, Prima LD, Chifari N, Napoli S, Russa CL et al. Avaliação do padrão de recuperação nutricional de crianças desnutridas
Comparison of anti-transglutaminase ELISAs and an anti-endomysial antibody atendidas no centro de recuperação e educação nutricional. Rev Ass Med
assay in the diagnosis of celiac disease: a prospective study. Clin Chem Brasil 1998;44:294-300.
2002;48:1546-50. 35. Trevisiol C, Brandt KG, Silva GA, Crovella S, Ventura A. High prevalence of
19. Lebenthal E, Branski D. Serum anti-endomysial and anti-tissue transglutaminase unrecognized celiac disease in an unselected Hospital Population in North-Eastern
for screening of celiac disease. Isr Med Assoc J 2002;4:627-8. Brasil (Recife, Pernambuco). J Pediatr Gastroenterol Nutr 2004;39:214-5.
20. Murdock AM, Johnston SD. Diagnostic criteria for coeliac disease: time for 36. Leffller DA, Kelly CP. Update on the evaluation and diagnosis of celiac disease.
change? Eur J Gastroenterol Hepatol 2005;17:41-3. Curr Opin Allergy Immunol 2006;6:191-6.
32 Rev Paul Pediatr 2009;27(1):28-32.